O10 STAT3 activation in peripheral blood MAIT cells is a predictive biomarker of response to biologics targeting the IL-23/IL-17 axis
Authors: Shane Solanky, Salma Khan, Isabella Tosi, Hannah Dawe, Wan Xinyu, Rosa Andres  Ejarque, Hira Bahadur Ale, Katarzyna Grys, Nick  Dand, Satveer Mahil, Michael R Barnes, Christopher E M Griffiths, Nick J Reynolds, Catherine H Smith, Richard B Warren, Jonathan  Barker, Paola Di Meglio
Journal: British Journal of Dermatology (2023)

Abstract The development of biologics, including the anti-interleukin (IL)-12/IL-23p40 ustekinumab and the anti-IL-17A secukinumab, has transformed the management of moderate-to-severe psoriasis and significantly improved patient well-being. Ustekinumab prevents IL-23 from interacting with its receptor, thus blocking the activation of signal transducer and activator of transcription 3 (STAT3) in T cells and the production of IL-17A. Secukinumab blocks the interaction between IL-17A and its receptor, preventing keratinocyte activation. Although both biologics are highly efficacious, the likelihood of an individual achieving a satisfactory clinical response is variable. Hence, there is a need for the identification of biomarkers predictive of clinical response to stratify patients and guide clinical decisions. We have previously found that IL-23-induced STAT3 translocation in mucosal associated invariant T (MAIT) cells of patients with psoriasis before therapy (baseline) is a candidate biomarker of clinical response to biologics specifically targeting the IL-23/IL-17 axis. STAT3 nuclear translocation was significantly lower in MAIT cells of ustekinumab patients not achieving a 75% reduction in Psoriasis Area Severity Index (PASI 75; i.e. nonresponders), and highly predictive of PASI 75 outcome with an optimal cutoff of 0.4 in receiver operating characteristic (ROC) curve analysis (discovery cohort n = 15). Moreover, STAT3 translocation was also significantly lower in patients not achieving a PASI 75 response to secukinumab. Here, we sought to investigate whether IL-17A production could be a more clinically scalable alternative to STAT3 translocation as a predictive biomarker. Although we observed a significantly (P &amp;lt; 0.05) reduced frequency of IL-17A-producing CD8 T cells after 12 weeks of ustekinumab treatment in PASI 75 responders, no differences in predictive value were identified at baseline. Next, we aimed to validate our findings in two independent cohorts of patients receiving biologics targeting IL-23. Firstly, we tested IL-23-induced STAT3 translocation in MAIT cells at baseline as predictive biomarker of clinical response to ustekinumab in an independent cohort of ustekinumab PASI 75 responders (n = 7) and PASI 75 nonresponders (n = 5). In keeping with the data generated in the discovery cohort, STAT3 translocation was statistically significantly lower in PASI 75 nonresponders compared with responders (RD 0.37 vs. 0.56; P &amp;lt; 0.01) and predicted PASI 75 response with 100% sensitivity and 85.7% specificity, after applying the ROC curve optimal cutoff identified in the discovery cohort. Finally, ongoing work is aimed at investigating whether IL-23-induced STAT3 translocation as a predictive biomarker can also be used in the context of the more recent and specific anti-IL-23p19 biologics. Taken together, we have identified IL-23-induced STAT3 translocation in MAIT cells as a predictive biomarker of response to biologics targeting the IL-23/IL-17 axis in psoriasis. Our findings pave the way for the future implementation of circulating predictive biomarkers for biologics targeting the IL-23/IL-17 axis in psoriasis and, potentially, in other inflammatory conditions.